Three major types of opioid receptors, .mu., .kappa. and .delta., are known and characterized. The identification of different opioid receptors has lead to efforts to develop specific ligands for these receptors. These ligands are known to be useful for at least two purposes:
a) to enable the more complete characterization of these different receptors, and PA1 b) to facilitate the identification of new analgesic drugs. PA1 R.sub.2 represents hydrogen, hydroxy, C.sub.1 -C.sub.6, alkoxy; C.sub.1 -C.sub.6 alkenyloxy; C.sub.7 -C.sub.16 arylalkyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyloxy is C.sub.1 -C.sub.6 alkyloxy; C.sub.7 -C.sub.16 arylalkenyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkenyloxy is C.sub.1 -C.sub.6 alkenyloxy; C.sub.1 -C.sub.6 alkanoxyloxy, C.sub.1 -C.sub.6 alkenoyloxy, C.sub.7 -C.sub.16 arylalkanoyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl, and the alkanoyloxy is C.sub.1 -C.sub.6 alkanoyloxy; PA1 R.sub.3 represents hydrogen, C.sub.6 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkenyl; C.sub.7 -C.sub.16 arylalkyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyl is C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.16 arylalkenyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkenyl is C.sub.1 -C.sub.6 alkenyl; hydroxy(C.sub.1 -C.sub.6)alkyl; alkoxyalkyl wherein the alkoxy is C.sub.1 -C.sub.6 alkoxy and the alkyl is C.sub.1 -C.sub.6 alkyl; CO.sub.2 H; CO.sub.2 (C.sub.1 -C.sub.6 alkyl); PA1 R.sub.4 is hydrogen, hydroxy; C.sub.1 -C.sub.6 alkoxy; C.sub.7 -C.sub.16 arylalkyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyloxy is C.sub.1 -C.sub.6 akyloxy; C.sub.1 -C.sub.6 alkenyloxy; C.sub.1 -C.sub.6 alkanoyloxy; C.sub.7 -C.sub.16 arylalkanoyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkanoyloxy is C.sub.1 -C.sub.6 alkanoyloxy; alkyloxyalkoxy wherein alkyloxy is C.sub.1 -C.sub.4 alkyloxy and alkoxy is C.sub.1 -C.sub.6 alkoxy; PA1 R.sub.5 and R.sub.6 each independently represent hydrogen; OH; C.sub.1 -C.sub.6 alkoxy; C.sub.1 -C.sub.6 alkyl; hydroxyalkyl wherein the alkyl is C.sub.1 -C.sub.6 alkyl; halo; nitro; cyano; thiocyanato; trifluoromethyl; CO.sub.2 H; CO.sub.2 (C.sub.1 -C.sub.6 alkyl); CONH.sub.2 ; CONH (C.sub.1 -C.sub.6 alkyl); CON(C.sub.1 -C.sub.6 alkyl).sub.2 ; amino; C.sub.1 -C.sub.6 monoalkyl amino; C.sub.1 -C.sub.6 dialkyl amino; C.sub.5 -C.sub.6 cycloalkylamnino; SH; SO.sub.3 H; SO.sub.3 (C.sub.1 -C.sub.6 alkyl); SO.sub.2 (C.sub.1 -C.sub.6 alkyl); SO.sub.2 NH.sub.2 ; SO.sub.2 NH(C.sub.1 -C.sub.6 alkyl); SO.sub.2 NH(C.sub.7 -C.sub.16 aryalkyl); SO(C.sub.1 -C.sub.6 alkyl); or R.sub.5 and R.sub.6 together form a phenyl ring which may be unsubstituted or substituted by halo, nitro, cyano, thiocyanato; C.sub.1 -C.sub.6 alkyl; trifluoromethyl; C.sub.1 -C.sub.6 alkoxy, CO.sub.2 H, CO(C.sub.1 -C.sub.6 alkyl), amino, C.sub.1 -C.sub.6 monoalkylamino, C.sub.1 -C.sub.6 dialkylamino, SH; SO.sub.3 H; SO.sub.3 (.sub.1 -C.sub.6 alkyl), SO.sub.2 (C.sub.1 -C.sub.6 alkyl), SO(C.sub.1 -C.sub.6 alkyl), and PA1 X represents oxygen; sulfur; CH.dbd.CH; or NR.sub.9 wherein R.sub.9 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl; C.sub.7 -C.sub.16 arylalkyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyl is C.sub.1 -C.sub.6 alkyl, C.sub.7 -C.sub.16 arylalkenyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkenyl is C.sub.1 -C.sub.6 alkenyl; C.sub.1 -C.sub.6 alkanoyl, and PA1 wherein aryl is unsubstituted or mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanato, trifluoromethyl, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, CO.sub.2 H, CONH.sub.2 CO.sub.2 (C.sub.1 -C.sub.3 alkyl), CONH(C.sub.1 -C.sub.3 alkyl), CON(C.sub.1 -C.sub.3 alkyl).sub.2 CO(C.sub.1 -C.sub.3 alkyl); amino; (C.sub.1 -C.sub.3 monoalkyl)amino, (C.sub.1 -C.sub.3 dialkyl)amino, C.sub.5 -C.sub.6 cycloalkylamino, (C.sub.1 -C.sub.3 alkanoyl)amido, SH, SO.sub.3 H, SO.sub.3 (C.sub.1 -C.sub.3 alkyl), SO.sub.2 (C.sub.1 -C.sub.3 alkyl), SO(C.sub.1 -C.sub.3 alkyl), C.sub.1 -C.sub.3 alkylthio or C.sub.1 -C.sub.3 alkanoylthio; PA1 and the pharmacologically acceptable salts of the compounds of the formula (I). PA1 R.sub.1 is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; PA1 R.sub.2 is selected from methoxy, ethoxy, n-propyloxy, benzyloxy, benzyloxy substituted in the aromatic ring with F, Cl, NO.sub.2, CN, CF.sub.3, CH.sub.3, OCH.sub.3, allyloxy, cinnamyloxy or 3-phenylpropoxy; PA1 R.sub.3 is selected from hydrogen, methyl, ethyl, benzyl or allyl; PA1 R.sub.4 is selected from hydroxy, methoxy, methoxymethoxy or acetyloxy; PA1 R.sub.5 and R.sub.6 are each and independently selected from hydrogen, nitro, cyano, chloro, fluoro, bromo, trifluoromethyl, CO.sub.2 H, CO.sub.2 CH.sub.3, CONH.sub.2, CONH CH.sub.3, SH, SO.sub.2 NH.sub.2, N(CH.sub.3).sub.2, SO.sub.2 CH.sub.3 and PA1 X is selected from O, NH, NCH.sub.3, N-benzyl, N-allyl. PA1 R.sub.1 is CH.sub.3 ; PA1 R.sub.2 is selected from methoxy, ethoxy, n-propyloxy, benzyloxy or benzyloxy substituted in the aromatic ring with chlorine PA1 R.sub.3 is selected from hydrogen or CH.sub.3 ; PA1 R.sub.4 is hydroxy; PA1 R.sub.5 and R.sub.6 are each and independently selected from hydrogen, CO.sub.2 H, CONH.sub.2, SO.sub.2 NH.sub.2, or SO.sub.2 CH.sub.3 ; and PA1 X is selected from O or NH. PA1 R.sub.2 is hydrogen; C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkenyl C.sub.7 -C.sub.16 arylalkyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyl is C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.16 arylalkenyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkenyl is C.sub.1 -C.sub.6 alkenyl; alkoxyalkyl wherein the alkoxy is C.sub.1 -C.sub.6 alkoxy and the alkyl is C.sub.1 -C.sub.6 alkyl; CO.sub.2 (C.sub.1 -C.sub.6 alkyl); PA1 which compounds in turn are reduced by catalytic hydrogenation using a catalyst such as palladium on charcoal and solvents such as methanol, ethanol, or glacial acetic acid to give compounds of formula (V) ##STR7## wherein R.sub.1 is C.sub.1 -C.sub.6 alkyl, C.sub.7 -C.sub.16 arylalkyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyl is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkanoyl, C.sub.7 -C.sub.16 arylalkanoyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkanoyl is C.sub.1 -C.sub.6 alkanoyl; PA1 which after N-demethylation using for instance chloroformates or cyanogen bromide followed by cleavage of the corresponding carbamates or N-cyano compounds (compounds of formula VIII) ##STR10## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above in formula (V) and (VII),
Analgesic drugs having specificity for an individual opioid receptor type have been demonstrated to have fewer side effects (e.g. respiratory depression, constipation, dependence), and in cases in which tolerance to one drug has developed, a second drug with different opioid receptor specificity may be effective. For example the successful substitution of DADLE (intrathecal application), a partially .delta.-selective analgesic peptide, for morphine in a human cancer patient with morphine tolerance has been demonstrated (E. S. Krames et al., Pain, Vol. 24:205-209, 1986). Evidence that a .delta.-selective agonist could be a potent analgesic with less tolerance and dependence liability was presented by Frederickson et al. (Science, Vol. 211:603-605, 1981). The peptide, D-Ala.sup.2,N-MeMet.sup.5 !enkephalin amide or "metkephanuid", was hundred fold more potent than morphine in the hot-plate test for analgesia after i. c. v. (intracerebral ventricular) administration. Naloxone precipitation of withdrawal after chronic administration of metkephamid and morphine in rats showed that metkephamid-treated animals exhibited fewer withdrawal symptoms than those given morphine, scoring only a little above the saline control group. Meltkephamid produced substantially less respiratory depression than morphine.
Another .delta.-selective peptide, D-Pen.sup.2, D-Pen.sup.5 !enkephalin (DPDPE) produces potent analgesic effects while showing little if any respiratory depression (C. N. May, Br.J. Pharmacol., Vol.98:903-913, 1989). DPDPE was found not to produce gastrointestinal side effects (e.g. constipation) (T. F.Burks, Life Sci., Vol.43:2177-2181, 1988). Since it is desireable that analgesics are stable against peptidases and are capable of entering the CNS easily, non-peptide analgesics are much more valuable.